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Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4.

Simpfendorfer KR, Strugnell RA, Brodnicki TC, Wijburg OL - PLoS ONE (2015)

Bottom Line: However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes.The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4.This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

ABSTRACT
Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces "hitchhiking" (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

No MeSH data available.


Related in: MedlinePlus

Congenic NOD mouse strains exhibit different diabetes incidences and localize Idd5.4.The cumulative incidence of diabetes was determined for age-matched cohorts for NOD and NOD.B6-Chr1 R7 females (A) and males (B); and age-matched cohorts for NOD, NOD.B6-Chr1 R0 and NOD.B6-Chr1 R2 females (C) and males (D). Congenic NOD mouse strains were homozygous for their respective B6-derived intervals. Pairwise comparisons of diabetes incidence curves were performed using the log-rank test: (A) ** P = 0.001; (B) *** P = 4.7x10-6. For panel (C) and (D), the P values were corrected for multiple testing (i.e. three comparisons): (C) 1: Holm-adjusted P = 0.09, 2: Holm-adjusted P = 0.09, 3**: P = 0.0002; (D) 1: Holm-adjusted P = 0.15, 2: Holm-adjusted P > 0.2, 3*: Holm adjusted P = 0.04.
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pone.0121979.g003: Congenic NOD mouse strains exhibit different diabetes incidences and localize Idd5.4.The cumulative incidence of diabetes was determined for age-matched cohorts for NOD and NOD.B6-Chr1 R7 females (A) and males (B); and age-matched cohorts for NOD, NOD.B6-Chr1 R0 and NOD.B6-Chr1 R2 females (C) and males (D). Congenic NOD mouse strains were homozygous for their respective B6-derived intervals. Pairwise comparisons of diabetes incidence curves were performed using the log-rank test: (A) ** P = 0.001; (B) *** P = 4.7x10-6. For panel (C) and (D), the P values were corrected for multiple testing (i.e. three comparisons): (C) 1: Holm-adjusted P = 0.09, 2: Holm-adjusted P = 0.09, 3**: P = 0.0002; (D) 1: Holm-adjusted P = 0.15, 2: Holm-adjusted P > 0.2, 3*: Holm adjusted P = 0.04.

Mentions: Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.


Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4.

Simpfendorfer KR, Strugnell RA, Brodnicki TC, Wijburg OL - PLoS ONE (2015)

Congenic NOD mouse strains exhibit different diabetes incidences and localize Idd5.4.The cumulative incidence of diabetes was determined for age-matched cohorts for NOD and NOD.B6-Chr1 R7 females (A) and males (B); and age-matched cohorts for NOD, NOD.B6-Chr1 R0 and NOD.B6-Chr1 R2 females (C) and males (D). Congenic NOD mouse strains were homozygous for their respective B6-derived intervals. Pairwise comparisons of diabetes incidence curves were performed using the log-rank test: (A) ** P = 0.001; (B) *** P = 4.7x10-6. For panel (C) and (D), the P values were corrected for multiple testing (i.e. three comparisons): (C) 1: Holm-adjusted P = 0.09, 2: Holm-adjusted P = 0.09, 3**: P = 0.0002; (D) 1: Holm-adjusted P = 0.15, 2: Holm-adjusted P > 0.2, 3*: Holm adjusted P = 0.04.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383422&req=5

pone.0121979.g003: Congenic NOD mouse strains exhibit different diabetes incidences and localize Idd5.4.The cumulative incidence of diabetes was determined for age-matched cohorts for NOD and NOD.B6-Chr1 R7 females (A) and males (B); and age-matched cohorts for NOD, NOD.B6-Chr1 R0 and NOD.B6-Chr1 R2 females (C) and males (D). Congenic NOD mouse strains were homozygous for their respective B6-derived intervals. Pairwise comparisons of diabetes incidence curves were performed using the log-rank test: (A) ** P = 0.001; (B) *** P = 4.7x10-6. For panel (C) and (D), the P values were corrected for multiple testing (i.e. three comparisons): (C) 1: Holm-adjusted P = 0.09, 2: Holm-adjusted P = 0.09, 3**: P = 0.0002; (D) 1: Holm-adjusted P = 0.15, 2: Holm-adjusted P > 0.2, 3*: Holm adjusted P = 0.04.
Mentions: Congenic strains names are abbreviated: R0 = NOD.B6-Chr1D1Mit48-D1Mit348Pigr-/-, R2 = NOD.B6-Chr1Pigr-D1Mit348Pigr-/-, R7 = NOD.B6-Chr1D1Mit48-D1Mit495. Diabetes incidence for congenic strains is described relative to NOD mice (>NOD or < NOD, based on Figs 1 and 3). Idd5.4a represents the B10-derived interval defined by Hunter et al. [25]; Idd5.4b represents the B6-derived interval, defined by the R7 congenic strain, that confers increased susceptibility to diabetes; IddX represents the B6-derived interval harboring the Pigr allele, defined by the R2 congenic strain, that confers protection against diabetes. Marker and gene positions are based on NCBI Bld37, mm9.

Bottom Line: However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes.The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4.This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

View Article: PubMed Central - PubMed

Affiliation: The Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.

ABSTRACT
Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces "hitchhiking" (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci.

No MeSH data available.


Related in: MedlinePlus